Chemokines are small secreted cytokines consisting of 8-14 kDa proteins, which can be classified into four groups according to the sequence of their conserved cysteine residues, CXC, CC, C and CX3C. They promote upregulation of cellular adhesion molecule, which enforces adhesion and lead to cell migration. Hence, the chemotactic cytokines play a crucial part in the recruitment and trafficking of leukocyte subsets.
Among the CC chemokines, MIP-1α and RANTES, known as ligands for CCR1, CCR3, CCR4 and CCR5 receptors, are involved in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis. This is strongly supported by the fact that CCR1 knockout mice show a significantly reduced incidence of disease in a mouse EAE model compared with the wild type mice. Studies by Karpus et al (J. Immunol. 1995, 155, 5003) further prove the pivotal role of MIP-1α in the same model of multiple sclerosis. It was shown that antibodies to MIP-1α prevented the development of both acute and relapsing paralytic disease as well as infiltration of mononuclear cells into the CNS.
In addition, there is strong evidence implicating RANTES in the pathophysiology of rheumatoid arthritits. For example, RANTES mRNA was detected in synovial tissue samples from patients with rheumatoid arthritis (Snowden, N. et al., Lancet, 1994, 343, 547). Further, antibodies to RANTES greatly reduced the development of disease in an adjuvant-induced arthritis model in the rat.
A number of studies have provided evidence for a role of CCR1 in allograft rejection. Combining a sub-nephrotoxic amount of cyclosporin A with blockade of chemokine receptors using a CCR1 antagonist has been shown to have a positive effect on solid allograft survival (Horuk, R. et al., J. Biol. Chem. 2001, 276, 4199).
Therefore, molecules that inhibit the interaction between the inflammatory chemokines and their receptor would be beneficial in the treatment of inflammatory, autoimmune, proliferative and hyperproliferative diseases.